Remodeling after myocardial infarction (MI) is a complex biological process that leads to progressive left ventricular dilation and clinical heart failure. Different therapies to limit or reverse post myocardial remodeling have been tested with limited success. Recently, cell-based therapies have been shown to hold promise of repairing an injured heart. However, the successful application of cell-based therapy remains hampered by a low rate of sustained cell engraftment which results from subsequent massive death of cells that have been initially retained in the target tissue. Thus, interventions to limit myocyte loss and enhance cardiac resident progenitor cell (CPC) survival and proliferation may provide important insights for designing new therapeutic strategies to treat heart failure. This proposal antagonizes the adverse cardiac remodeling induced after MI through inhibition of neutrophil-derived serine proteases (NSPs), proteases that are released by inflammatory cells upon their activation at site of injury. We have shown that NSPs induce myocyte detachment and apoptosis by anoikis through degradation of key proteins involved in cell adhesion and myocyte contractile function. Pilot study shows that NSP deletion in-vivo using DiPeptidyl Peptidase I (DPPI) KO mice, mice that lack major NSPs, attenuated myocyte death following MI and resulted in smaller infarct size and preserved cardiac function. Interestingly, we found that DPPI deletion also increased the capability of cardiac regeneration and repair of the injured myocardium, suggesting that NSPs negatively affect progenitor cell survival and proliferation in response to cardiac ischemic insult. Using cultured c-kit positive CPCs, we found that NSPs alter c-kit receptor stability and turnover through ubiquitylation and proteasomal degradation of c-kit receptors. These data support the hypothesis that NSPs are key modulators of c-kit receptor stability and turnover, limit cardiac resident progenitor cell survival and proliferation n area of inflammation and reduce their capability to replace myocardial tissue after MI. Here we will elucidate the signaling pathways downstream from NSPs that are critical for mediating c- kit signaling alterations and CPC death. Furthermore, we propose to investigate the mechanisms by which DPPI blockade therapy affects repair after myocardial infarction. The significance of the proposed work is to determine if effective administration of DPPI blocker could be performed safely to reduce myocyte loss, to enhance cardiac regeneration and to replace myocardial tissue after MI.